OBJECTIVE: To describe and analyze, utilizing a case study approach, the U.S.- Mexico Border Diabetes Prevention and Control Project, a health research cooperation initiative incorporating the participation of federal, state, and local institutions of both countries. METHODS: A model of equal representation, participation, consensus, and shared leadership was used, with the participation of more than 130 institutions. A sample of 4 020 people over 18 years of age was obtained by a random, multistage, stratified, clustered design. A questionnaire about diabetes mellitus type 2 (DM2) and health was applied. The statistical analysis took into account the design effect. RESULTS: The prevalence of diagnosed DM2 was 14.9% (95% confidence interval [95% CI]: 12.5-17.6) and the prevalence of diagnosed DM2 adjusted by age was 19.5% (95% CI: 16.8-22.6) on the Mexican side of the border and 16.1% (IC95%: 13.5-19.2) on the U.S. border side. There were differences between the DM2 prevalence and risk factors along the border. CONCLUSIONS: The U.S.-Mexico Border Diabetes Prevention and Control Project allowed the border zone between the two countries to be considered, for the first time ever, as a unit for epidemiological research. A shared understanding among all participating institutions and entities of sociopolitical structures and procedures is required for effective border health cooperation initiatives.